NRF2 Biomarkers Study

Study titleDeveloping Clinical Biomarkers Of NRF2 Activation For Therapeutic Application In Neurodegenerative Disease
UK Chief InvestigatorProfessor Dame Pamela Shaw
Research summaryNeurodegenerative diseases such as Alzheimer's disease (AD) and motor neurone disease (ALS/MND) cause cell death of different populations of nerve cells. These conditions are very distressing for sufferers and their families. There is a severe lack of treatments available to slow disease progression and clinical trials have had high failure rates partly because there is no way to demonstrate that a drug is reaching the nervous system in the right amounts to protect the nerve cells from injury.

Although the underlying causes that trigger these diseases are complex (multiple genes and environmental factors), there is substantial overlap in the cell pathways that lead to neurodegeneration.

This project is focused on a master cellular pathway (sometimes called the programmed cell-life pathway) controlled by a molecule, NRF2, that promotes cell survival in the face of stresses such as oxidative stress, inflammation, and failure of the energy-generating and protein quality-control pathways within nerve cells, which are known to contribute to neurodegeneration. Our aim is to develop MRI imaging and body fluid markers to show NRF2-activating drugs working in the body. These results will be applied later in clinical trials to test the effectiveness of NRF2 activators for patients with MND and AD.

The study will recruit 30 patients with MND and 30 controls (healthy people or people with non-neurodegenerative diseases); and each participant will be asked to attend two study visits – Baseline and approximately 4 months later.

Study procedures at each visit will be the same (to assess how things have changed over time), and include:
• MRI scan of the brain
• Lumbar puncture (LP) to collect cerebrospinal fluid (CSF)
• Blood samples
• Skin sample (only required at one study visit).
Inclusion/exclusion criteriaINCLUSION CRITERIA
• Participants over the age of 18 years.
• Ability to give informed consent. If the participant is unable to provide written consent due to physical disability, an independent witness will be present at the informed consent discussion and sign the consent form on the participant’s behalf.

Additional inclusion criteria for patients with MND only:
• Patients will have a clinical diagnosis of MND made by a consultant neurologist meeting El Escorial possible, probable or definite criteria.
• Stability on or off riluzole treatment for 28 days prior to entering study.

• A contraindication to MRI (for example, pacemakers or other metallic implants), pregnancy, any significant co-existent neuromuscular disease or chronic medical illness.
• A contraindication to lumbar puncture (for example, any clinical concerns in regard to raised intracranial pressure, bleeding diathesis, significant coagulation abnormalities on blood screening, treatment with anticoagulants, local skin infections at entry site).
• The presence of respiratory failure impairing ability to lie flat in scanner (on clinical grounds and/or based on slow vital capacity).
• Diagnosis of an additional neurodegenerative disease unrelated to MND spectrum disorder

Additional exclusion criteria for controls only:
• Diagnosis of a neurodegenerative disease.
Riluzole administration is not an exclusion criterion. The duration of treatment will be recorded.
Current statusClosed to Recruitment, follow-up complete
Contact detailsLiam Haslam on 0114 231 339 /
or Lee Tuddenham on 0114 222 2263 /
Recruitment group(s)Participant groups:
1. Patients with MND
2. Controls without MND or any other neurodegenerative disease. Controls may be healthy participants or patients with incidental neurological complaints, for example thunderclap headache, who are undergoing lumbar puncture. Both groups will be assessed at two time-points. The control group will be age- and sex-matched to the patient group to ensure there are no statistical differences between groups.
Recruitment target(s)30 MND patients and 20 controls.
Key datesActual opening date: 09 October 2018
Recruitment planned end date: 03 July 2020
Closed to recruitment date: 07 June 2021
Funder(s)Medical Research Council (MRC) Centres of Excellence in Neurodegeneration (CoEN).
SponsorSheffield Teaching Hospitals NHS Foundation Trust
Study designObservational (Clinical Laboratory Study)
Intervention (if applicable)Not applicable
Phase (if applicable)Not applicable
Outcome measuresPrimary outcome: variability and test-retest reliability measurements of 1H-MRS measurements of glutathione, blood and CSF biomarkers.
Publications / Results reportsLinks will be provided when papers are published.
Participant Information SheetInformation Sheet - Patients
Information Sheet - Controls